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. 2017 Dec;22(12):1444-1450.
doi: 10.1634/theoncologist.2016-0488. Epub 2017 Oct 27.

ALK Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy

Jeffrey S Ross  1   2 , Siraj M Ali  3 , Omotayo Fasan  4 , Jared Block  5 , Sumanta Pal  6 , Julia A Elvin  3 , Alexa B Schrock  3 , James Suh  3 , Sahar Nozad  2 , Sungeun Kim  2 , Hwa Jeong Lee  2 , Christine E Sheehan  2 , David M Jones  2 , Jo-Anne Vergilio  3 , Shakti Ramkissoon  3 , Eric Severson  3 , Sugganth Daniel  3 , David Fabrizio  3 , Garrett Frampton  3 , Vince A Miller  3 , Philip J Stephens  3 , Laurie M Gay  3
Affiliations

ALK Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy

Jeffrey S Ross et al. Oncologist. 2017 Dec.

Abstract
in English, Chinese

Background: Genomic fusions of the anaplastic lymphoma kinase gene (ALK) are a well-established therapy target in non-small cell lung cancer (NSCLC). From a survey of 114,200 clinical cases, we determined the prevalence of ALK rearrangements (rALK) in non-NSCLC tumors and report their responsiveness to therapies targeting ALK.

Materials and methods: Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay.

Results: Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with ALK fusions (fALK) or rALK, 675 (77.1%) were NSCLC and 201 (22.9%) were other tumor types. ALK fusions were significantly more frequent in NSCLC (3.1%) than non-NSCLC (0.2%; p < .0001). Patients with non-NSCLC tumors harboring fALK were significantly younger (p < .0001) and more often female (p < .0001) than patients with fALK-positive NSCLC. EML4 was more often the fusion partner in NSCLC (83.5%) versus non-NSCLC tumors (30.9%; p < .0001).

Conclusion: ALK rearrangements can be identified in a wide variety of epithelial and mesenchymal malignancies beyond NSCLC. Anti-ALK therapies can be effective in non-NSCLC tumors driven by fALK, and further study of therapies targeting ALK in clinical trials involving a wider variety of cancer types appears warranted.

Implications for practice: Rearrangements involving the ALK gene have been detected in dozens of cancer types using next-generation sequencing. Patients whose tumors harbor ALK rearrangements or fusions respond to treatment with crizotinib and alectinib, including tumors not normally associated with ALK mutations, such as non-Langerhans cell histiocytosis or renal cell carcinoma. Comprehensive genomic profiling using next-generation sequencing can detect targetable ALK fusions irrespective of tumor type or fusions partner.

摘要

背景.间变性淋巴瘤激酶基因（ALK）融合是非小细胞肺癌（NSCLC）治疗的确定靶点。根据对114 200例临床病例展开的调查, 我们确定了非NSCLC肿瘤患者中ALK重排（rALK）的发生率, 并报告了他们对靶向ALK的疗法的反应。

材料与方法.通过基于杂交捕获和适配器连接的下一代测序法对114 200例复发及转移性恶性肿瘤患者（包括实体瘤和淋巴造血系统癌）进行了全面的基因组测序。

结果.在这114 200例临床病例中, 21 522例（18.8%）罹患NSCLC, 92 678例（81.2%）罹患其他类型肿瘤。876例（0.8%）患者出现ALK融合（fALK）或rALK, 其中675例（77.1%）罹患NSCLC, 201例（22.9%）罹患其他类型肿瘤。NSCLC患者（3.1%）中ALK融合的发生率明显高于非NSCLC患者（0.2%）（p < 0.0001）。与fALK‐阳性 NSCLC患者相比, 负荷fALK的非NSCLC患者的年龄明显更小（p < 0.0001）, 并且女性患者的比例通常更高（p < 0.0001）。NSCLC患者（83.5%）中出现融合伴侣EML4的比例通常高于非NSCLC患者（30.9%; p < 0.0001）。

结论.除NSCLC外, 多种上皮和间质恶性肿瘤中均存在ALK重排。抗ALK疗法可有效治疗fALK驱动的非NSCLC肿瘤, 因此, 有必要在涉及各类癌症的临床试验中对靶向ALK的疗法进行进一步研究。

对临床实践的启示：下一代测序技术已被使用对多种癌症类型进行了ALK基因重排检测。负荷ALK重排或融合的肿瘤患者对克唑替尼和alectinib治疗产生反应, 其中包括通常无ALK突变的肿瘤, 例如, 非朗格罕组织细胞增多症或肾细胞癌。使用下一代测序技术进行的全面基因组测序可检测靶向ALK融合, 而这与肿瘤类型或融合伴侣无关。

Keywords: ALK; Alectinib; Comprehensive genomic profiling; Crizotinib; Fusion; Rearrangement.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
Mutation frequencies of genes coaltered with ALK fusions. Note that cases may have both ALK fusions and ALK nonfusion alterations in the same tumor. All cases feature at least a single ALK fusion genomic alteration. Abbreviation: NSCLC, non‐small cell lung cancer.
Figure 2.
Figure 2.
A series of positron emission tomography scans showing a robust and sustained response to a crizotinib‐based treatment regimen. The patient received cervical radiotherapy, one cycle of chemotherapy (cytoxan 750 mg/m2, etoposide 100 mg/m2 days 1–3, and prednisone 100 mg days 1–5), and crizotinib 250 mg daily from July 2015 to present. Shown here are scans taken prior to treatment initiation (far left) and at 20 weeks (center) and 35 weeks (right) after treatment initiation.
Figure 3.
Figure 3.
A representative response in a mesenteric lymph node to alectinib for a patient with renal cell carcinoma harboring an EML4‐ALK fusion.
See this image and copyright information in PMC

References

    1. Chiarle R, Voena C, Ambrogio C et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008;8:11–23. - PubMed
    1. Barreca A, Lasorsa E, Riera L et al. Anaplastic lymphoma kinase in human cancer. J Mol Endocrinol 2011;47:R11–R23. - PubMed
    1. Mano H. The EML4‐ALK oncogene: Targeting an essential growth driver in human cancer. Proc Jpn Acad Ser B Phys Biol Sci 2015;91:193–201. - PMC - PubMed
    1. Hallberg B, Palmer RH. The role of the ALK receptor in cancer biology. Ann Oncol 2016;27(suppl 3):iii4–iii15. - PubMed
    1. Zhao Z, Verma V, Zhang M. Anaplastic lymphoma kinase: Role in cancer and therapy perspective. Cancer Biol Ther 2015;16:1691–1701. - PMC - PubMed

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